Projectsummary Currently, no technology exists that has been specifically designed to allow high precision noninvasive neuromodulationandneuroimaginginawakeanimals.Ultrasoundisanidealmodalitytofillthisvoidsinceithas been used (1) directly for neuromodulation, (2) for functional imaging of cerebral blood flow, and (3) tolocally activate drugs. However, many barriers remain before ultrasound is fully developed as an ideal tool for neuroscience. In this proposal, we will create next generation ultrasound methods to allow high precision noninvasive neuromodulation (directly and with novel ultrasound-triggered particles) and functional neuroimaginginawakenon-humanprimates(NHPs).Wewilldevelopnewprocedurestoenableplacementof asmall(<0.3cm3)ultrasoundfocusatawell-definedlocationinthebrainofanawakeNHP.Ourdevelopments will overcome limitations of current methods that have limited accuracy or require working within the MR environment which is not compatible with behaving NHPs. We propose multiple innovations that will make focusedultrasound(FUS)neuromodulationcompatiblewithawakeNHPswhilemaintainingmm-scaleaccuracy. Theultrasoundfocuswillbetunedinasinglereal-timeMRIguidancesessionusingtimereversalmethods.We willapplythissystemtotargettheNHPlateralprefrontalcortex(lPFC)andhippocampus(HPC),whichplaykey roles for attention and memory functions compromised in many diseases. We will test direct FUS neuromodulationusingasensitiveattentionandlearningparadigmdevelopedbyco-PIWomelsdorf.Usingthe samehardwareplatform,wewillimplementfunctionalultrasoundimaging(f-USI),whichisanemergingblood flow imaging method that is capable of mapping blood flow similar to functional MRI but is not commercially available.Wewillimplementandoptimizef-USImethodsforuseincognitiveneurosciencestudiesofprefrontal cortexfunctioninawake,behavingNHPs.Ultrasoundisahighbandwidthmodalitycapableofgeneratingmultiple gigabytesofdataperminute,sothisaimwillrequireustodevelopsoftwaretoacquire,reconstruct,andpost- processf-USIimages.Atthecompletionofourfirsttwoaims,wewillhaveasingleultrasoundsystemcapable of delivering a small ultrasound focus in a behaving NHPs and imaging cerebral blood flow. We will use this newlydevelopedcapabilityinathirdaimtoactivateneuromodulatorydrugsfromaparticlerecentlydeveloped by co-PI Airan. These novel nanoparticles carry the anesthetic propofol and are biologically inactive until they undergoaphasetransitioncausedbyanultrasoundpulse.Whencombinedwiththeprototypeultrasoundsystem wearedeveloping,this?phase-change?oruncagingofthepropofolwillallowlocalizeddeliveryoftheanesthetic triggeredbyultrasound.WewilloptimizetheuseofthisnovelFUS-triggeredneuromodulationmethodtoinhibit theHPCandlPFCwhileNHPsperformalearningtask,enablingidentificationofprecisefunctionalcontributions of these areas for attentional control and memory. At the completion of the proposed study, we will have developednovelultrasoundmethodstomodulateandimagetheawakeNHPbrain.